The present invention relates to an improved process for the preparation of enantiomerically pure (5,5xe2x80x2-dichloro-6,6xe2x80x2-dimethoxybiphenyl-2,2xe2x80x2-diyl)-bis(diphenylphosphine -oxides) starting from 5-bromo-2-chloro-anisole and phosphorus oxychlorides of the type Oxe2x95x90P(phenyl)2(Cl).
Such bis-diphenylphosphine oxides can be reduced to give the corresponding bis-diphenylphosphines, which are used as ligands for metal complexes. Such metal complexes are for their part of importance as catalysts for enantioselective hydrogenations (see DE-A1 195 22 293 and the corresponding U.S. Pat. No. 5,710,339 and 5,801,261).
Likewise known from this literature is a multi-stage process for the preparation of enantiomerically pure (5,5xe2x80x2-dichloro-6,6xe2x80x2-dimethoxybiphenyl-2,2xe2x80x2-diyl)-bis(diphenylphosphine oxides). In this process, in a first stage, 5-bromo-2-chloroanisole is reacted by a selective monometalation with a phosphorus oxychloride of the type Oxe2x95x90P(phenyl)2(Cl), giving a (4-chloro-3-methoxyphenyl)diphenylphosphine oxide. The metalation is carried out with magnesium in tetrahydrofuran, the phosphorus oxychloride is used as a solution in tetrahydrofuran, and the product is isolated by concentrating a solution in methylene chloride by evaporation and stirring with tert-butyl methyl ether. The product is produced in a yield of 70%.
In a second stage, the (4-chloro-3-methoxyphenyl)diphenyl-phosphine oxide is converted into the corresponding 2-iodo compound.
For this purpose, lithium diisopropylamide, dissolved in tetrahydrofuran, is added to a solution of the starting phosphine oxide in tetrahydrofuran at xe2x88x9270xc2x0 C., the mixture is heated to 0xc2x0 C., cooled to xe2x88x9276xc2x0 C., and then, at this temperature, a solution of iodine in tetrahydrofuran is added dropwise. Work-up is carried out by treating with aqueous sodium sulfite solution, then extracting with ethyl acetate and stripping off the extractant. This gives the product in a yield of 80%.
In a third stage, the (4-chloro-2-iodo-3-methoxyphenyl)diphenyl-phosphine oxide is reacted with copper powder in dimethylformamide over the course of 16 hours to give racemic (5,5xe2x80x2-dichloro-6,6xe2x80x2-dimethoxybiphenyl-2,2xe2x80x2-diyl)-bis(diphenylphosphine oxide). The latter compound is isolated by filtration, removal of the dimethylformamide from the filtrate, and stirring with tert-butyl methyl ether.
Finally, in a fourth stage, the racemic (5,5xe2x80x2-dichloro-6,6xe2x80x2-dimethoxy-biphenyl-2,2-diyl)-bis(diphenylphosphine oxide) is separated into its enantiomers using enantiomerically pure mono- or dicarboxylic acids. Here, both forms of enantiomerically pure mono- or dicarboxylic acid have to be used one after the other and complex extractions and filtrations have to be carried out.
The known overall process for the preparation of the bis-diphenyl-phosphine oxides is disadvantageous, not very suitable, and uneconomic for use on a relatively large scale, since it produces products in unsatisfactory yields, in many cases requires partly toxic solvents, is very complicated in terms of process engineering, requires the use of very low temperatures (down to xe2x88x9276xc2x0 C.) and long reaction times, and requires the use of large amounts of solvents and auxiliaries.
There is therefore still the need for a process for the preparation of such bis-diphenylphosphine oxides, with which the latter are accessible in a more simple, more efficient and more cost-effective manner, and with which a preparation on a relatively large scale can also be carried out without problems.
We have now found a process for the preparation of enantiomerically pure bis-diphenylphosphine oxides of the formula (I) 
in which
R1 is phenyl, naphthyl, heteroaryl having 4 or 5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or cyclohexyl, wherein each R1 is optionally substituted by Rxe2x80x2, ORxe2x80x2, NO2, NH2, NHRxe2x80x2, or NRxe2x80x22 in which each Rxe2x80x2is C1-C6-alkyl,
R2 is C1-C4-alkoxy,
R3 is hydrogen, fluorine, chlorine, or bromine, and
R4 and R5, independently of one another, are hydrogen, fluorine, chlorine, bromine, C1-C6-alkyl, or C1-C6-alkoxy,
comprising
(1) in a first stage, selectively monometalating a bromine compound of the formula 
xe2x80x83in which R2 to R5 have the meanings given for formula (I), in a solvent comprising a mixture of tetrahydrofuran and an aromatic hydrocarbon and reacting the resultant metalated compound with a diphenylphosphinic chloride of the formula (II) 
xe2x80x83in which R1 has the meaning given for formula (I), which is added without solvent to the metalated compound, to give a diphenylphosphine oxide of the formula (III) 
xe2x80x83in which R1 to R5 have the meanings given in formula (I), which is isolated from a solution in an aromatic hydrocarbon by adding a saturated aliphatic hydrocarbon,
(2) in a second stage, metalating the diphenylphosphine oxide of the formula (III) in the 6-position and reacting the resultant metalated compound with iodine at a temperature of not less than xe2x88x9225xc2x0 C., wherein the metalated diphenylphosphine oxide of the formula (III) and iodine are metered in simultaneously such that a small amount of iodine is always present in excess, to give a 2-iodo-diphenyl-phosphine oxide of the formula (IV) 
xe2x80x83in which R1 to R5 have the meanings given for formula (I), which is separated off in dissolved form in an aromatic hydrocarbon,
(3) in a third stage, converting the 2-iodo-diphenylphosphine oxide of the formula (IV) with copper (preferably dendritic copper) in an aromatic hydrocarbon solvent into a racemic bis-diphenylphosphine oxide of the formula (I), which is crystallized from absolution in an aromatic hydrocarbon, and
(4) in a fourth stage, separating the racemic bis-diphenylphosphine oxide of the formula (I) into its enantiomers by crystallization with an enantiomerically pure mono- or dicarboxylic acid, wherein a first enantiomer is obtained by crystallization from a solution in an aromatic hydrocarbon and a second enantiomer is obtained by hydrolysis and subsequent crystallization from a solution in an aromatic hydrocarbon.
In the formulas (I) to (IV), R1 is preferably unsubstituted phenyl, unsubstituted naphthyl, heteroaryl having 4 or 5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of oxygen and sulfur, or unsubstituted cyclohexyl.
In the formulas (I), (IIa), (III) and (IV)
R2 is preferably methoxy,
R3 is preferably fluorine, chlorine, or bromine (particularly chlorine), and
R4 and R5 are preferably hydrogen.
The aromatic hydrocarbons are, for example, benzene, toluene, or xylenes. Preference is given to toluene.
The saturated aliphatic hydrocarbons may, for example, be those having boiling points of more than 30xc2x0 C. (at atmospheric pressure). Preference is given to straight-chain or branched pentanes, hexanes, heptanes, and octanes. Particular preference is given to n-pentane.
In the first stage, the metalation can be carried out, for example, using magnesium, which can be activated, where necessary, for example, by adding a small amount of iodine. For the metalation, it is possible to use, for example, 1 to 1.5 mol of magnesium, based on 1 mol of bromine compound of the formula (IIa). The solvent mixture to be used for the metalation can comprise, for example, 20 to virtually 100% by volume of tetrahydrofuran and brought to 100% by volume using aromatic hydro-carbon. The solvent mixture preferably comprises 40 to 60% by volume (particularly 45 to 55% by volume) of tetrahydrofuran and brought to 100% by volume using aromatic hydrocarbon.
The procedure can be carried out, for example, by additionally introducing magnesium, a small amount of iodine, and the solvent mixture, heating the mixture to a temperature in the range from 30 to 80xc2x0 C., then metering in a bromine compound of the formula (IIa) dissolved in the same solvent mixture at a temperature in the range from 30 to 80xc2x0 C. and, where appropriate, when the metered addition is complete, refluxing further, e.g., for 5 to 60 minutes. The phosphinic chloride of the formula (II) is then added not in dissolved form but without a diluent, for example, with cooling to temperatures in the range from xe2x88x9210 to +15xc2x0 C. Finally, the mixture can be further after-stirred, for example, for 30 to 250 minutes, at temperatures in the range from 0 to 30xc2x0 C.
The reaction mixture present after the first stage has been carried out can be worked up, for example, by pouring it onto iced water, separating off the organic phase, extracting the aqueous phase with an aromatic hydrocarbon, combining the organic phase and the extract, washing with dilute aqueous alkaline solution and water, and concentrating by evaporation. Advantageously, the aim is a solution of the prepared diphenylphosphine oxide of the formula (III) in and aromatic hydrocarbon that is as concentrated as possible but from which no solid constituents precipitate. According to the invention, a saturated aliphatic hydrocarbon is then added and after, for example, 5 to 20 hours, the formed, readily filterable precipitate is filtered off, optionally after-washed with the saturated aliphatic hydrocarbon, and dried.
In this way, it is possible to obtain a diphenylphosphine oxide of the formula (III) in the form of a white powder in yields of more than 80% and in purities of more than 92%. By dispensing with the addition of the phosphinic chloride of the formula (II) in a solvent, it is possible to work overall with less solvent, thus saving on solvent and achieving a higher space-time yield.
In the second stage, the metalating agent used may be, for example, butyllithium or lithium diisopropylamide. The latter is preferred.
The procedure may involve, for example, initially introducing the diphenylphosphine oxide of the formula (III) in a solvent, e.g., tetrahydro-furan, cooling it to, for example, xe2x88x9225 to 0xc2x0 C., and, at this temperature, metering in the metalating agent, e.g., dissolved in tetrahydrofuran containing hydrocarbons, such that the temperature can be maintained in the range from xe2x88x9225 to 0xc2x0 C. by cooling. This gives a solution (A). Separately, a solution of iodine in, for example, tetrahydrofuran can be prepared and also cooled to, for example, xe2x88x9225 to 0xc2x0 C. This gives a solution (B). Then, a reaction vessel is charged with a small amount of solvent, e.g., tetrahydro-furan, and at, for example, xe2x88x9225 to 0xc2x0 C., and then, at, for example, xe2x88x9225 to 0xc2x0 C., solution (A) and solution (B) are metered in simultaneously such that a small amount of iodine is always present in excess. This can be readily checked from the color of the reaction mixture. Dark colors indicate an iodine excess. The temperature is preferably maintained at xe2x88x9225xc2x0 C. to xe2x88x921 0xc2x0 C. during the reaction. To complete the reaction, following the metered addition of solutions (A) and (B), it is possible, where appropriate, to after-stir for a further, for example, 10 to 150 minutes at, for example, xe2x88x9210 to +10xc2x0 C. Thereafter, excess iodine that is still present is expediently removed, e.g., by adding a dilute aqueous solution of sodium thiosulfate.
The reaction mixture present after the second stage has been carried out can be worked up, for example, by first separating off the organic phase, extracting the remaining aqueous phase with an extractant, e.g., an aromatic hydrocarbon, where necessary, washing the organic phase combined with the extract with water, and concentrating by evaporation. In this way, it is possible to obtain 2-iodo-diphenylphosphine oxides of the formula (IV) in yields of more than 90% and in the form of, for example, 15 to 30% strength by weight solutions in an aromatic hydro-carbon. Such solutions can be used directly in the third process stage.
The second process stage carried out according to the invention is characterized by the use of temperatures that can be maintained with little technical expenditure, shortened metered addition times, yield increases, and a simple work-up option.
In the third stage, a dendritic copper is preferably used, as described in Glossary of Terms Relating to Particle Technology, Edition 1 st May 1996. Such copper can have an average particle size of, for example, 1 to 100 xcexcm (preferably 30 to 50 xcexcm), a surface area of, for example, 0.04 to 1 m2/g (preferably 0.07 to 0.5 m2/g), and a purity of more than 99.5% (preferably more than 99.7%). Dendritic copper to be used according to the invention is available commercially.
The procedure may involve, for example, initially introducing dendritic copper together with the aromatic hydrocarbon and, at a temperature of, for example, 70 to 140xc2x0 C., metering in the solution of a 2-iodo-diphenylphosphine oxide of the formula (IV) obtained in the second stage. It is possible to use, for example, 1 to 10 mol (preferably 2 to 8 mol) of dendritic copper per mole of 2-iodo-diphenylphosphine oxide of the formula (IV). When the metered addition is complete, it is possible, where necessary, to after-stir for a further 1 to 5 hours at 70 to 140xc2x0 C. The metered addition and after-stirring time can together be, for example, 3 to 8 hours. For work-up,it is possible, for example, to filter the hot reaction mixture, to wash the filter cake with a solvent, e.g., a chlorinated hydro-carbon, to evaporate the washing solution to dryness, to add the solid obtained to the filtrate, and to heat this mixture to reflux temperature. It is also possible to after-wash the filter cake with an aromatic hydrocarbon heated, for example, to 70 to 140xc2x0 C., to add this wash solution to the first filtrate, and to heat the mixture to reflux temperature. Where appropriate, it is possible to remove some of the aromatic hydrocarbon, e.g., by distillation. Upon cooling to, for example, 0 to 25xc2x0 C., the prepared racemic bis-diphenylphosphine oxide of the formula (I) then precipitates out and can be collected, for example, by filtration and subsequent drying, where necessary, in a vacuum and at elevated temperature.
The third reaction stage carried out according to the invention is characterized by the use of cost-effective and low-toxicity solvents, by simple work-up, and shorter reaction times.
In the fourth stage, it is possible, for example, to react, at elevated temperature, the racemic bis-diphenylphosphine oxide of the formula (I) dissolved, for example, in a chlorinated hydrocarbon, with a solution of a pure enantiomer of dibenzoyltartaric acid, for example, in an ester, and to cool the reaction mixture slowly, for example, over the course of from 2 to 6 hours, to 10 to 25xc2x0 C. In the process, a salt precipitates out that can be separated off, for example by filtration.
The salt can be further processed, for example, by taking it up in an aromatic hydrocarbon, washing it with dilute aqueous acid and dilute aqueous base, then heating the organic phase to boiling and evaporating off or adding just enough aromatic hydrocarbon such that a virtually saturated solution is present at elevated temperature. After cooling, for example, to 10 to 30xc2x0 C., the one enantiomerically pure form of the bis-diphenylphosphine oxide of the formula (I) that crystallizes out can be separated off. This generally gives the product with an enantiomer excess ee of more than 99%.
The filtrate from the work-up following the reaction with a pure enantiomer of dibenzoyltartaric acid can be worked up initially in a manner similar to the salt taken up with an aromatic hydrocarbon, for example, by washing it directly with dilute acid and then with dilute aqueous base. By changing the solvent, e.g., to an aromatic hydrocarbon, concentrating by evaporation, and cooling, it is possible to obtain a solid that is a racemic feed material. From the filtrate from the separation of the racemic feed material, it is possible, by further concentration by evaporation and cooling, to obtain the second enantiomer of the bis-phenylphosphine oxide of the formula (I) generally with an enantiomer excess ee of more than 99%.
The fourth process stage according to the invention is characterized by a saving of approximately 50% of enantiomerically pure mono- or dicarboxylic acid and a simple work-up.
If enantiomerically pure bis-diphenylphosphine oxide of the formula (I) prepared according to the invention is to be reduced to the corresponding bis-diphenylphosphine, this can be achieved in a known manner, for example, using trichlorosilane as reducing agent in accordance with the literature given in the introduction above.
The following examples further illustrate details for the process of this invention. The invention, which is set forth in the foregoing disclosure, is not to be limited either in spirit or scope by these examples. Those skilled in the art will readily understand that known variations of the conditions of the following procedures can be used. Unless otherwise noted, all temperatures are degrees Celsius and all percentages are percentages by weight.